Arylation Of Indoles Research Articles

Ascorbic Acid as an Aryl Radical Inducer in the Gold-Mediated Arylation of Indoles with Aryldiazonium Chlorides.

In recent years interest in the development of protocols that facilitate the oxidative addition of gold to access mild cross-coupling processes mediated by this metal has increased. In this context, we report herein that ascorbic acid, a natural and readily accessible antioxidant, can be used to accelerate the oxidative addition of aryldiazonium chlorides onto AuI . The aryl-AuIII species generated in this way, has been used to prepare 3-arylindoles in a one-pot protocol starting from anilines and para-, meta-, and ortho- substituted aryldiazonium chlorides. The mechanism underlying the oxidative addition has been examined in detail based on EPR analyses, cyclic voltammetry, and DFT calculations. Interestingly, we have found that in this protocol, the chloride atom induces the AuII /AuIII oxidation step.

Cover Feature: Ascorbic Acid as an Aryl Radical Inducer in the Gold‐Mediated Arylation of Indoles with Aryldiazonium Chlorides (Chem. Eur. J. 3/2020)

Cover Feature: Ascorbic Acid as an Aryl Radical Inducer in the Gold‐Mediated Arylation of Indoles with Aryldiazonium Chlorides (Chem. Eur. J. 3/2020)

Synthesis of a Diaryliodonium Salt and Its Use in the Direct Arylation of Indole: A Two-Step Experiment for the Organic Teaching Laboratory

In the past decade, C–H functionalization has been a very active topic of research in both academia and industry. When a H atom is replaced by an aryl (or heteroaryl) group, the transformation is t...

Synthesis, biological evaluation, and docking study of indole aryl sulfonamides as aromatase inhibitors

In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0–72 h), starting from a concentration of 100 μM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.

Nickel-Catalyzed C(2)-H Arylation of Indoles with Aryl Chlorides under Neat Conditions.

Nickel-catalyzed regioselective C(2)-H arylation of indoles and pyrroles with aryl chlorides is achieved under neat conditions. This method allows the efficient coupling of diverse aryl chlorides employing a user-friendly and inexpensive Ni(OAc)2/dppf catalyst system at 80 °C. Numerous functionalities, such as halides, alkyl ether, fluoro-alkyl ether, and thioether, and substituted amines, including heteroarenes like benzothiazolyl, pyrrolyl, indolyl, and carbazolyl, are well tolerated under the reaction conditions. The preliminary mechanistic study highlights a single-electron transfer (SET) pathway for the arylation reaction.

Synthesis of Indoles through Domino Reactions of 2‐Fluorotoluenes and Nitriles

Indoles are essential heterocycles in medicinal chemistry, and therefore, novel and efficient approaches to their synthesis are in high demand. Among indoles, 2-aryl indoles have been described as privileged scaffolds. Advanced herein is a straightforward, practical, and transition-metal-free assembly of 2-aryl indoles. Simply combining readily available 2-fluorotoluenes, nitriles, LiN(SiMe3 )2 , and CsF enables the generation of a diverse array of indoles (38 examples, 48-92 % yield). A range of substituents can be introduced into each position of the indole backbone (C4 to C7, and aryl groups at C2), providing handles for further elaboration.

Facile synthesis of 3-aryl benzofurans, 3-aryl benzothiophenes, 2-aryl indoles and their dimers

The preparation of 3-aryl benzofuran and benzothiophenes and their dimers at 2-position and, 2-aryl indoles and their 3-position dimers preparation is described.

Addition of a Carbene Catalyst to Indole Aryl Aldehyde Activates a Remote δ-sp2 Carbon for Protonation and Formal [4+2] Reaction.

The addition of a carbene catalyst to an indole aryl aldehyde leads to the activation of a remote sp2 carbon that is five atoms away from the catalyst. The unsaturated Breslow intermediate formed between the catalyst and substrate undergoes an internal redox reaction and remote carbon protonation to generate an analogous azolium vinyl enolate intermediate. Subsequent [4+2] reaction with cyclic imine substrates eventually affords multicyclic pyridoindoles as nearly single diastereomers with excellent enantioselectivities.

A Three-Component Strategy for Benzoselenophene Synthesis under Metal-Free Conditions Using Selenium Powder.

An efficient three-component benzoselenophenes formation has been developed from substituted indoles, acetophenones, and selenium powder under metal-free conditions. 2-Aryl indoles played an important role to promote benzoselenophene formation from acetophenone derivatives and selenium powder. One C-C and two C-Se bonds were selectively formed to provide 40 new benzoselenophenes in good yields.

A Kinetic Study of the Step of Aryl Halide Activation in a Direct Arylation Reaction of Indole under Real Catalysis Conditions

This paper presents the results of a kinetic study on the step of activation of aryl iodides and aryl bromides under conditions of ligand-free catalysis in the direct arylation of indole at a C–H bond performed using an analysis of the integral kinetic curves of consumption of the competing aryl halides. In the course of an experiment under the conditions of competition between a pair of aryl halides having different reactivity, an acceleration in the consumption of a less active substrate was observed, which coincided in time with the almost complete consumption of a more active one. The experimental data unambiguously indicated a rapid character of the stage of oxidative addition with the participation of not only reactive aryl iodides but also nonactivated aryl bromides.

Potassium tert-Butoxide-Mediated Condensation Cascade Reaction: Transition Metal-Free Synthesis of Multisubstituted Aryl Indoles and Benzofurans.

An efficient and facile method to synthesize valuable disubstituted 2-aryl indoles and benzofurans in good yields has been demonstrated, based on a tert-butoxide-mediated condensation reaction involving a vinyl sulfoxide intermediate. Products are obtained from N- or O-benzyl benzaldehydes using dimethyl sulfoxide as a carbon source. The methodology features a wide functional group tolerance and transition metal-free environment. Preliminary mechanistic studies suggest that the reaction involves a tandem aldol reaction/Michael addition/dehydrosulfenylation/isomerization sequence through an ionic protocol.

A micellar catalysis strategy applied to the Pd-catalyzed C–H arylation of indoles in water

Surfactant-assisted, ligand-enabled selective C–H arylation of indoles in water under mild conditions using 1 mol% of [(cinnamyl)PdCl]2.

Synthesis of C2-tetrasubstituted indolin-3-ones via Cu-catalyzed oxidative dimerization of 2-aryl indoles and cross-addition with indoles.

An efficient protocol for the synthesis of 2,2-disubstituted indolin-3-ones under mild conditions has been developed. This reaction involves the copper-catalyzed in situ oxidative de-aromatization of 2-arylindoles to indol-3-one, followed by self-dimerization as well as cross-addition with indoles under mild conditions. The result generates a wide variety of C2-tetrasubstituted indolin-3-ones with good to high yields (62–82%).

Rhodium-catalyzed, P-directed selective C7 arylation of indoles.

The indole scaffold will continue to play a vital role in the future of drug discovery and agrochemical development. Regioselective direct arylation of indoles on the benzenoid moiety is a challenging task due to the inherent reactivity of the C2 and C3 positions. Here, we have developed an effective strategy for the regioselective direct arylation of indoles at the C7 position with (hetero)aryl bromides by the rational design of a directing group. The key to the high selectivity and reactivity of this method is the appropriate selection of a class of directing groups, N-PR2 (R = t Bu and c Hex), that are easily removed in the presence of the Wilkinson's catalyst. Using the present method as a key step, formal synthesis of marine alkaloid dictyodendrin B has also been demonstrated.

Directing Effects on the Copper-Catalyzed Site-Selective Arylation of Indoles.

Different site selectivities have been reported for indoles with different directing groups in copper-catalyzed site-selective C-H arylations. Computational and mass spectrometric studies have been conducted in an effort to understand the origin of site selectivity and the effects of the directing groups. A Heck-like mechanism involving a four-membered ring is found in all three of the cases studied. For N-acetyl indole with a weak directing group, a neutral Heck-like mechanism is controlled by an electronic effect resulting in C2 site selectivity. In contrast, indole with a N-P(O) tBu2 group and N-benzyl-3-pivaloyl indole prefer a cationic Heck-like reaction in which a favorable six-membered chelation between the directing group and the CuIII center determines the C6 and C5 site selectivities.

Chemoselective N-H or C-2 Arylation of Indole-2-carboxamides: Controllable Synthesis of Indolo[1,2- a]quinoxalin-6-ones and 2,3'-Spirobi[indolin]-2'-ones.

Novel methods involving the chemoselective N-H or C-2 arylation for the synthesis of indolo[1,2- a]quinoxalin-6-ones and 2,3'-spirobi[indolin]-2'-ones starting from indole-2-carboxamides were developed. When reactions were carried out using ZnI2 as catalyst and Ag2CO3 as oxidant, indolo[1,2- a]quinoxalin-6-ones were synthesized in up to 86% yields via intramolecular N-H/C-H coupling, whereas the dearomative cyclization reactions were realized in the presence of TfOH, resulting in C-2 arylation of indole through C-H functionalization or a Fridel-Crafts alkylation reaction to give 2,3'-spirobi[indolin]-2'-ones in moderate to excellent yields.

Mechanistic Study of Direct Arylation of Indole Using Differential Selectivity Measurements: Shedding Light on the Active Species and Revealing the Key Role of Electrophilic Substitution in the Catalytic Cycle

Differential selectivity of the direct arylation of indole with aryl halides under competing and noncompeting conditions with a varying set of reaction parameters was determined using phase trajectories. The results described herein allow for conclusions to be drawn regarding the character of active complexes (cationic, neutral, or anionic) as well as realization of the indole electrophilic substitution in the catalytic cycle using the ligand-free catalytic system.

Exploration of Biaryl Carboxylic Acids as Proton Shuttles for the Selective Functionalization of Indole C-H Bonds.

A survey of diversely substituted 2-arylbenzoic acids were synthesized and tested for use as proton shuttle in the direct arylation of indoles with bromobenzenes. It was found that 3-ethoxy-2-phenylbenzoic acid gives superior yield and selectivity for this class of substrates.

SiO2-functionalized melamine-pyridine group–supported Cu(OAc)2 as an efficient heterogeneous and recyclable nanocatalyst for the N-arylation of amines through Ullmann coupling reactions

This study reports a convenient approach to prepare SiO 2 /CCPy/Cu(OAc) 2 as a novel nanocatalyst, in which melamine-bearing pyridine groups have functionalized SiO 2 and can act as a capping agent to stabilize Cu(II) species. The catalyst is characterized through Fourier transform infrared, transmission electron microscopy, field emission scanning electron microscopy (FESEM), Brunauer–Emmett–Teller (BET), thermogravimetric analysis, inductivity coupled plasma (ICP), and energy dispersive X-ray (EDX) techniques. Furthermore, its catalytic behavior is evaluated in the N -arylation of indole, imidazole, and aniline during Ullmann-type C–N coupling reactions. Moreover, it has been proved that the heterogeneous nanocatalyst can be feasibly recovered by filtration and reused in five consecutive reaction cycles without any noticeable loss of its catalytic activity. The results clarified that the devised method is advantageous from several perspectives, that is, low catalyst loading, high product yield, experimental simplicity, broad substrate scope, and short reaction time.

Pd‐Catalyzed C‐H/N‐H Arylation: One‐Pot Synthesis of Indolo[1, 2‐f]phenanthridines

AbstractA novel Pd‐catalyzed method for the synthesis of indolo[1, 2‐f]phenanthridines from 2‐bromo‐2′‐iodo‐1,1′‐biphenyl and indole derivatives has been reported. The reaction involves direct N−H and C2‐H arylation of indole. This Pd‐catalyzed double arylation provides a useful route to synthesize indolo[1, 2‐f]phenanthridine derivatives from simple and readily accessible starting materials.